Risk of adverse events following the initiation of antihypertensives in older people with complex health needs: a self-controlled case series in the United Kingdom.

BACKGROUND: We assessed the risk of adverse events-severe acute kidney injury (AKI), falls and fractures-associated with use of antihypertensives in older patients with complex health needs (CHN). SETTING: UK primary care linked to inpatient and mortality records. METHODS: The source population comprised patients aged >65, with ≥1 year of registration and unexposed to antihypertensives in the year before study start. We identified three cohorts of patients with CHN, namely, unplanned hospitalisations, frailty (electronic frailty index deficit count ≥3) and polypharmacy (prescription of ≥10 medicines). Patients in any of these cohorts were included in the CHN cohort. We conducted self-controlled case series for each cohort and outcome (AKI, falls, fractures). Incidence rate ratios (IRRs) were estimated by dividing event rates (i) during overall antihypertensive exposed patient-time over unexposed patient-time; and (ii) in the first 30 days after treatment initiation over unexposed patient-time. RESULTS: Among 42,483 patients in the CHN cohort, 7,240, 5,164 and 450 individuals had falls, fractures or AKI, respectively. We observed an increased risk for AKI associated with exposure to antihypertensives across all cohorts (CHN: IRR 2.36 [95% CI: 1.68-3.31]). In the 30 days post-antihypertensive treatment initiation, a 35-50% increased risk for falls was found across all cohorts and increased fracture risk in the frailty cohort (IRR 1.38 [1.03-1.84]). No increased risk for falls/fractures was associated with continuation of antihypertensive treatment or overall use. CONCLUSION: Treatment with antihypertensives in older patients was associated with increased risk of AKI and transiently elevated risk of falls in the 30 days after starting antihypertensive therapy.

Drug utilization analysis of osteoporosis medications in seven European electronic health databases.

We studied the characteristics of patients prescribed osteoporosis medication and patterns of use in European databases. Patients were mostly female, older, had hypertension. There was suboptimal persistence particularly for oral medications. Our findings would be useful to healthcare providers to focus their resources on improving persistence to specific osteoporosis treatments. PURPOSE: To characterise the patients prescribed osteoporosis therapy and describe the drug utilization patterns. METHODS: We investigated the treatment patterns of bisphosphonates, denosumab, teriparatide, and selective estrogen receptor modulators (SERMs) in seven European databases in the United Kingdom, Italy, the Netherlands, Denmark, Spain, and Germany. In this cohort study, we included adults aged ≥ 18 years, with ≥ 1 year of registration in the respective databases, who were new users of the osteoporosis medications. The study period was between 01 January 2018 to 31 January 2022. RESULTS: Overall, patients were most commonly initiated on alendronate. Persistence decreased over time across all medications and databases, ranging from 52-73% at 6 months to 29-53% at 12 months for alendronate. For other oral bisphosphonates, the proportion of persistent users was 50-66% at 6 months and decreased to 30-44% at 12 months. For SERMs, the proportion of persistent users at 6 months was 40-73% and decreased to 25-59% at 12 months. For parenteral treatment groups, the proportions of persistence with denosumab were 50-85% (6 month), 30-63% (12 month) and with teriparatide 40-75% (6 month) decreasing to 21-54% (12 month). Switching occurred most frequently in the alendronate group (2.8-5.8%) and in the teriparatide group (7.1-14%). Switching typically occurred in the first 6 months and decreased over time. Patients in the alendronate group most often switched to other oral or intravenous bisphosphonates and denosumab. CONCLUSION: Our results show suboptimal persistence to medications that varied across different databases and treatment switching was relatively rare.

Characterising complex health needs and the use of preventive therapies in the older population: a population-based cohort analysis of UK primary care and hospital linked data.

BACKGROUND: While several definitions exist for multimorbidity, frailty or polypharmacy, it is yet unclear to what extent single healthcare markers capture the complexity of health-related needs in older people in the community. We aimed to identify and characterise older people with complex health needs based on healthcare resource use (unplanned hospitalisations or polypharmacy) or frailty using large population-based linked records. METHODS: In this cohort study, data was extracted from UK primary care records (CPRD GOLD), with linked Hospital Episode Statistics inpatient data. People aged > 65 on 1st January 2010, registered in CPRD for ≥ 1 year were included. We identified complex health needs as the top quintile of unplanned hospitalisations, number of prescribed medicines, and electronic frailty index. We characterised all three cohorts, and quantified point-prevalence and incidence rates of preventive medicines use. RESULTS: Overall, 90,597, 110,225 and 116,076 individuals were included in the hospitalisation, frailty, and polypharmacy cohorts respectively; 28,259 (5.9%) were in all three cohorts, while 277,332 (58.3%) were not in any (background population). Frailty and polypharmacy cohorts had the highest bi-directional overlap. Most comorbidities such as diabetes and chronic kidney disease were more common in the frailty and polypharmacy cohorts compared to the hospitalisation cohort. Generally, prevalence of preventive medicines use was highest in the polypharmacy cohort compared to the other two cohorts: For instance, one-year point-prevalence of statins was 64.2% in the polypharmacy cohort vs. 60.5% in the frailty cohort. CONCLUSIONS: Three distinct groups of older people with complex health needs were identified. Compared to the hospitalisation cohort, frailty and polypharmacy cohorts had more comorbidities and higher preventive therapies use. Research is needed into the benefit-risk of different definitions of complex health needs and use of preventive therapies in the older population.

Classification of patients with osteoarthritis through clusters of comorbidities using 633 330 individuals from Spain.

OBJECTIVES: To explore clustering of comorbidities among patients with a new diagnosis of OA and estimate the 10-year mortality risk for each identified cluster. METHODS: This is a population-based cohort study of individuals with first incident diagnosis of OA of the hip, knee, ankle/foot, wrist/hand or 'unspecified' site between 2006 and 2020, using SIDIAP (a primary care database representative of Catalonia, Spain). At the time of OA diagnosis, conditions associated with OA in the literature that were found in ≥1% of the individuals (n = 35) were fitted into two cluster algorithms, k-means and latent class analysis. Models were assessed using a range of internal and external evaluation procedures. Mortality risk of the obtained clusters was assessed by survival analysis using Cox proportional hazards. RESULTS: We identified 633 330 patients with a diagnosis of OA. Our proposed best solution used latent class analysis to identify four clusters: 'low-morbidity' (relatively low number of comorbidities), 'back/neck pain plus mental health', 'metabolic syndrome' and 'multimorbidity' (higher prevalence of all studied comorbidities). Compared with the 'low-morbidity' cluster, the 'multimorbidity' cluster had the highest risk of 10-year mortality (adjusted hazard ratio [HR]: 2.19 [95% CI: 2.15, 2.23]), followed by the 'metabolic syndrome' cluster (adjusted HR: 1.24 [95% CI: 1.22, 1.27]) and the 'back/neck pain plus mental health' cluster (adjusted HR: 1.12 [95% CI: 1.09, 1.15]). CONCLUSION: Patients with a new diagnosis of OA can be clustered into groups based on their comorbidity profile, with significant differences in 10-year mortality risk. Further research is required to understand the interplay between OA and particular comorbidity groups, and the clinical significance of such results.

Oral Bisphosphonates Are Associated With Increased Risk of Severe Acute Kidney Injury in Elderly Patients With Complex Health Needs: A Self-Controlled Case Series in the United Kingdom.

Although oral bisphosphonates (BP) are commonly used, there is conflicting evidence for their safety in the elderly. Safety concerns might trump BP use in older patients with complex health needs. Our study evaluated the safety of BP, focusing on severe acute kidney injury (AKI), gastrointestinal ulcer (GI ulcer), osteonecrosis of the jaw (ONJ), and femur fractures. We used UK primary care data (Clinical Practice Research Datalink [CPRD GOLD]), linked to hospital (Hospital Episode Statistics [HES] inpatient) and ONS mortality data. We included all patients aged >65 with complex health needs and no BP use in the year before study start (January 1, 2010). Complex health needs were defined in three cohorts: an electronic frailty index score ≥3 (frailty cohort), one or more unplanned hospitalization/s (hospitalization cohort); and prescription of ≥10 different medicines in 2009 (polypharmacy cohort). Incidence rates were calculated for all outcomes. Subsequently, all individuals who experienced AKI or GI ulcer anytime during follow-up were included for Self-Controlled Case Series (SCCS) analyses. Incidence rate ratios (IRRs) were estimated separately for AKI and GI ulcer, comparing event rates between BP-exposed and unexposed time windows. No SCCS were conducted for ONJ and femur fractures. We identified 94,364 individuals in the frailty cohort, as well as 78,184 and 95,621 persons in the hospitalization and polypharmacy cohorts. Of those, 3023, 1950, and 2992 individuals experienced AKI and 1403, 1019, and 1453 had GI ulcer/s during follow-up, respectively. Age-adjusted SCCS models found evidence of increased risk of AKI associated with BP use (frailty cohort: IRR 1.65; 95% confidence interval [CI], 1.25-2.19), but no association with GI ulcers (frailty cohort: IRR 1.24; 95% CI, 0.86-1.78). Similar results were obtained for the hospitalization and polypharmacy cohorts. Our study found a 50% to 65% increased risk of AKI associated with BP use in elderly patients with complex health needs. Future studies should further investigate the risk-benefit of BP use in these patients. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Bariatric surgery increases the rate of major fracture: self-controlled case series study in UK Clinical Practice Research Datalink.

Conflicting results exist about the relationship between bariatric surgery and fracture risk. Also, prediction of who is at increased risk of fracture after bariatric surgery is not currently available. Hence, we used a combination of a self-controlled case series (SCCS) study to establish the association between bariatric surgery and fracture, and develop a prediction model for postoperative fracture risk estimation using a cohort study. Patients from UK Primary care records from the Clinical Practice Research Datalink GOLD linked to Hospital Episode Statistics undergoing bariatric surgery with body mass index (BMI) ≥30 kg/m2 between 1997 and 2018 were included in the cohort. Those sustaining one or more fractures in the 5 years before or after surgery were included in the SCCS. Fractures were considered in three categories: (i) any except skull and digits (primary outcome); (ii) major (hip, vertebrae, wrist/forearm, and humerus); and (iii) peripheral (forearm and lower leg). Of 5487 participants, 252 (4.6%) experienced 272 fractures (of which 80 were major and 135 peripheral) and were included in the SCCS analyses. Major fracture risk increased after surgery, incidence rate ratios (IRRs) and 95% confidence intervals (CIs): 2.77 (95% CI, 1.34-5.75) and 3.78 (95% CI, 1.42-10.08) at ≤3 years and 3.1 to 5 years postsurgery when compared to 5 years prior to surgery, respectively. Any fracture risk was higher only in the 2.1 to 5 years following surgery (IRR 1.73; 95% CI, 1.08-2.77) when compared to 5 years prior to surgery. No excess risk of peripheral fracture after surgery was identified. A prediction tool for major fracture was developed using 5487 participants included in the cohort study. It was also internally validated (area under the receiver-operating characteristic curve [AUC ROC] 0.70) with use of anxiolytics/sedatives/hypnotics and female as major predictors. Hence, major fractures are nearly threefold more likely after bariatric surgery. A simple prediction tool with five variables identifies high risk patients for major fracture. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

What influences patients' opinion of remission and low disease activity in psoriatic arthritis? Principal component analysis of an international study.

OBJECTIVE: In PsA, the treatment objective is remission or low disease activity (LDA), but patients' perception of remission is poorly studied. This analysis aimed to identify factors associated with patient-defined remission. METHODS: This analysis uses ReFlaP data, an international PsA study, with remission defined as 'At this time, is your psoriatic arthritis in remission, if this means: you feel your disease is as good as gone?'. Variables associated with, first, patient-defined remission and, second, LDA were identified using multivariable logistic regression and principal component analysis (PCA) to explore correlated variables. RESULTS: Of 424 patients (50.2% male, mean age 52 years) with established disease, 94 (22.2%) reported themselves as being in remission and 191 (45.0%) as LDA alone. In multivariable analysis pain, psoriasis, impact of disease, physician opinion of symptoms from joint damage and Groll comorbidity index were independent predictors of remission. For LDA, results were similar. Using PCA, variance explained was 74% by five components for men and 80% by six components for women. The key component from PCA for remission was, for both sex, disease impact (Psoriatic Arthritis Impact of Disease, pain and HAQ) explaining 22.2-27.5% of variance. Other factors included musculoskeletal disease activity, chronicity/joint damage, psoriasis, enthesitis and CRP. For LDA, similar factors were identified but the variance explained was lower (64-68%). CONCLUSION: Many factors impact on patients' opinion of remission, dominated by disease impact. Disease activity in multiple domains, chronicity/age, comorbidities and symptoms due to other conditions contribute to a robust model highlighting that patient-defined remission is multifaceted. TRIALS REGISTRATION: Clinicaltrials.gov, http://clinicaltrials.gov, NCT03119805.

Bisphosphonates to reduce bone fractures in stage 3B+ chronic kidney disease: a propensity score-matched cohort study.

BACKGROUND: Bisphosphonates are contraindicated in patients with stage 4+ chronic kidney disease. However, they are widely used to prevent fragility fractures in stage 3 chronic kidney disease, despite a lack of good-quality data on their effects. OBJECTIVES: The aims of each work package were as follows. Work package 1: to study the relationship between bisphosphonate use and chronic kidney disease progression. Work package 2: to study the association between using bisphosphonates and fracture risk. Work package 3: to determine the risks of hypocalcaemia, hypophosphataemia, acute kidney injury and upper gastrointestinal events associated with using bisphosphonates. Work package 4: to investigate the association between using bisphosphonates and changes in bone mineral density over time. DESIGN: This was a new-user cohort study design with propensity score matching. SETTING AND DATA SOURCES: Data were obtained from UK NHS primary care (Clinical Practice Research Datalink GOLD database) and linked hospital inpatient records (Hospital Episode Statistics) for work packages 1-3 and from the Danish Odense University Hospital Databases for work package 4. PARTICIPANTS: Patients registered in the data sources who had at least one measurement of estimated glomerular filtration rate of < 45 ml/minute/1.73 m2 were eligible. A second estimated glomerular filtration rate value of < 45 ml/minute/1.73 m2 within 1 year after the first was requested for work packages 1 and 3. Patients with no Hospital Episode Statistics linkage were excluded from work packages 1-3. Patients with < 1 year of run-in data before index estimated glomerular filtration rate and previous users of anti-osteoporosis medications were excluded from work packages 1-4. INTERVENTIONS/EXPOSURE: Bisphosphonate use, identified from primary care prescriptions (for work packages 1-3) or pharmacy dispensations (for work package 4), was the main exposure. MAIN OUTCOME MEASURES: Work package 1: chronic kidney disease progression, defined as stage worsening or starting renal replacement. Work package 2: hip fracture. Work package 3: acute kidney injury, hypocalcaemia and hypophosphataemia identified from Hospital Episode Statistics, and gastrointestinal events identified from Clinical Practice Research Datalink or Hospital Episode Statistics. Work package 4: annualised femoral neck bone mineral density percentage change. RESULTS: Bisphosphonate use was associated with an excess risk of chronic kidney disease progression (subdistribution hazard ratio 1.12, 95% confidence interval 1.02 to 1.24) in work package 1, but did not increase the probability of other safety outcomes in work package 3. The results from work package 2 suggested that bisphosphonate use increased fracture risk (hazard ratio 1.25, 95% confidence interval 1.13 to 1.39) for hip fractures, but sensitivity analyses suggested that this was related to unresolved confounding. Conversely, work package 4 suggested that bisphosphonates improved bone mineral density, with an average 2.65% (95% confidence interval 1.32% to 3.99%) greater gain in femoral neck bone mineral density per year in bisphosphonate users than in matched non-users. LIMITATIONS: Confounding by indication was a concern for the clinical effectiveness (i.e. work package 2) data. Bias analyses suggested that these findings were due to inappropriate adjustment for pre-treatment risk. work packages 3 and 4 were based on small numbers of events and participants, respectively. CONCLUSIONS: Bisphosphonates were associated with a 12% excess risk of chronic kidney disease progression in participants with stage 3B+ chronic kidney disease. No other safety concerns were identified. Bisphosphonate therapy increased bone mineral density, but the research team failed to demonstrate antifracture effectiveness. FUTURE WORK: Randomised controlled trial data are needed to demonstrate antifracture efficacy in patients with stage 3B+ chronic kidney disease. More safety analyses are needed to characterise the renal toxicity of bisphosphonates in stage 3A chronic kidney disease, possibly using observational data. STUDY REGISTRATION: This study is registered as EUPAS10029. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 17. See the NIHR Journals Library website for further project information. The project was also supported by the National Institute for Health Research Biomedical Research Centre, Oxford.

RATIONALE AND AIMS: Bisphosphonates are used to prevent fractures in people with fragile bones. People with chronic kidney disease have a high risk of fracturing, but the safety and effectiveness of bisphosphonates in severe chronic kidney disease is unclear. The aim of this study was to assess the benefits (e.g. bone strength improvement and fracture prevention) and the risks of unwanted effects associated with bisphosphonates for people with moderate to severe chronic kidney disease. METHODS: Anonymised primary and secondary care electronic medical records data from the UK NHS were used, as well as a Danish equivalent that included bone density scans. Anyone in these databases with a measure of reduced kidney function that suggested moderate to severe chronic kidney disease was eligible, which was > 220,000 people from the UK. Over 20,000 of them used bisphosphonates. Bisphosphonate users were matched to non-users with similar age, sex and other characteristics. RESULTS: Bisphosphonate users had a 12% higher risk of their chronic kidney disease getting worse than non-users. Their risks of other side effects, such as acute kidney injuries and gastrointestinal problems, did not change. Bisphosphonate users had a 25% higher risk of fractures than non-users in the UK database, probably because the matching methods did not create similar-enough groups of users and non-users. However, it was found that bisphosphonate improved bone density in the Danish database. Bone density is a proxy for bone strength, so better bone density should mean fewer fractures. CONCLUSIONS: These results suggest that bisphosphonate therapy may make moderate to severe chronic kidney disease worse. More studies are needed on how bisphosphonates affect milder chronic kidney disease. Bisphosphonates were associated with better bone strength, but it could not be demonstrated that they reduced fracture risk. More data are required, probably from a placebo-controlled trial, to determine whether or not bisphosphonates prevent fractures in people with moderate to severe chronic kidney disease and whether or not this is worth the risk of their chronic kidney disease worsening.

Estimating the population health burden of musculoskeletal conditions using primary care electronic health records.

OBJECTIVES: Better indicators from affordable, sustainable data sources are needed to monitor population burden of musculoskeletal conditions. We propose five indicators of musculoskeletal health and assessed if routinely available primary care electronic health records (EHR) can estimate population levels in musculoskeletal consulters. METHODS: We collected validated patient-reported measures of pain experience, function and health status through a local survey of adults (≥35 years) presenting to English general practices over 12 months for low back pain, shoulder pain, osteoarthritis and other regional musculoskeletal disorders. Using EHR data we derived and validated models for estimating population levels of five self-reported indicators: prevalence of high impact chronic pain, overall musculoskeletal health (based on Musculoskeletal Health Questionnaire), quality of life (based on EuroQoL health utility measure), and prevalence of moderate-to-severe low back pain and moderate-to-severe shoulder pain. We applied models to a national EHR database (Clinical Practice Research Datalink) to obtain national estimates of each indicator for three successive years. RESULTS: The optimal models included recorded demographics, deprivation, consultation frequency, analgesic and antidepressant prescriptions, and multimorbidity. Applying models to national EHR, we estimated that 31.9% of adults (≥35 years) presenting with non-inflammatory musculoskeletal disorders in England in 2016/17 experienced high impact chronic pain. Estimated population health levels were worse in women, older aged and those in the most deprived neighbourhoods, and changed little over 3 years. CONCLUSION: National and subnational estimates for a range of subjective indicators of non-inflammatory musculoskeletal health conditions can be obtained using information from routine electronic health records.

Safety of Oral Bisphosphonates in Moderate-to-Severe Chronic Kidney Disease: A Binational Cohort Analysis.

Bisphosphonates are the first-line treatment for preventing fractures in osteoporosis patients. However, their use is contraindicated or to be used with caution in chronic kidney disease (CKD) patients, primarily because of a lack of information about their safety and effectiveness. We aimed to investigate the safety of oral bisphosphonates in patients with moderate to severe CKD, using primary-care electronic records from two cohorts, CPRD GOLD (1997-2016) and SIDIAP (2007-2015) in the UK and Catalonia, respectively. Both databases were linked to hospital records. SIDIAP was also linked to end-stage renal disease registry data. Patients with CKD stages 3b to 5, based on two or more estimated glomerular filtration rate measurements less than 45 mL/min/1.73 m2 , aged 40 years or older were identified. New bisphosphonate users were propensity score-matched with up to five non-users to minimize confounding within this population. Our primary outcome was CKD stage worsening (estimated glomerular filtration rate [eGFR] decline or renal replacement therapy). Secondary outcomes were acute kidney injury, gastrointestinal bleeding/ulcers, and severe hypocalcemia. Hazard ratios (HRs) were estimated using Cox regression and Fine and Gray sub-HRs were calculated for competing risks. We matched 2447 bisphosphonate users with 8931 non-users from CPRD and 1399 users with 6547 non-users from SIDIAP. Bisphosphonate use was associated with greater risk of CKD progression in CPRD (sub-HR [95% CI]: 1.14 [1.04, 1.26]) and SIDIAP (sub-HR: 1.15 [1.04, 1.27]). No risk differences were found for acute kidney injury, gastrointestinal bleeding/ulcers, or hypocalcemia. Hence, we can conclude a modest (15%) increased risk of CKD progression was identified in association with bisphosphonate use. No other safety concerns were identified. Our findings should be considered before prescribing bisphosphonates to patients with moderate to severe CKD. © 2020 American Society for Bone and Mineral Research (ASBMR).

Serious complications and risk of re-operation after Dupuytren's disease surgery: a population-based cohort study of 121,488 patients in England.

Dupuytren's disease (DD) is a common fibro-proliferative disorder of the palm. We estimated the risk of serious local and systemic complications and re-operation after DD surgery. We queried England's Hospital Episode Statistics database and included all adult DD patients who were surgically treated. A longitudinal cohort study and self-controlled case series were conducted. Between 1 April 2007 and 31 March 2017, 121,488 adults underwent 158,119 operations for DD. The cumulative incidence of 90-day serious local complications was low at 1.2% (95% CI 1.1-1.2). However, the amputation rate for re-operation by limited fasciectomy following dermofasciectomy was 8%. 90-day systemic complications were also uncommon at 0.78% (95% CI 0.74-0.83), however operations routinely performed under general or regional anaesthesia carried an increased risk of serious systemic complications such as myocardial infarction. Re-operation was lower than previous reports (33.7% for percutaneous needle fasciotomy, 19.5% for limited fasciectomy, and 18.2% for dermofasciectomy). Overall, DD surgery performed in England was safe; however, re-operation by after dermofasciectomy carries a high risk of amputation. Furthermore, whilst serious systemic complications were unusual, the data suggest that high-risk patients should undergo treatment under local anaesthesia. These data will inform better shared decision-making regarding this common condition.

Alendronate use and bone mineral density gains in women with moderate-severe (stages 3B-5) chronic kidney disease: an open cohort multivariable and propensity score analysis from Funen, Denmark.

Bisphosphonates are contraindicated in moderate-to-severe chronic kidney disease patients. However, they are used to prevent fragility fractures in patients with impaired kidney function, despite a lack of evidence on their effects on bone density in these patients. We demonstrated that Alendronate had a positive effect on bone in these patients. PURPOSE: This study aimed to assess the association between alendronate use and bone mineral density (BMD) change in subjects with moderate-severe chronic kidney disease (CKD). METHODS: We created a cohort of CKD stage 3B-5 patients by linking all DXA-based measurements in the Funen area, Denmark, to biochemistry, national health registries and filled prescriptions. Exposure was dispensation of alendronate and the outcome was annualized percentage change in BMD at the femoral neck, total hip and lumbar spine. Individuals were followed from first BMD to the latest of subsequent DXA measurements. Alendronate non-users were identified using incidence density sampling and matched groups were created using propensity scores. Linear regression was used to estimate average differences in the annualized BMD. RESULTS: Use of alendronate was rare in this group of patients: propensity score matching (PSM) resulted in 71 alendronate users and 142 non-users with stage 3B-5 CKD (as in the 1 year before DXA). Whilst alendronate users gained an average 1.07% femoral neck BMD per year, non-users lost an average of 1.59% per annum. The PSM mean differences in annualized BMD were + 2.65% (1.32%, 3.99%), + 3.01% (1.74%, 4.28%) and + 2.12% (0.98%, 3.25%) at the femoral neck, total hip and spine BMD, respectively, all in favour of alendronate users. CONCLUSION: In a real-world cohort of women with stage 3B-5 CKD, use of alendronate appears associated with a significant improvement of 2-3% per year in the femoral neck, total hip and spine BMD. More data are needed on the anti-fracture effectiveness and safety of bisphosphonate therapy in moderate-severe CKD.

Antibiotic treatment and flares of rheumatoid arthritis: a self-controlled case series study analysis using CPRD GOLD.

There is emerging evidence of the impact of infections on rheumatoid arthritis pathogenesis and flares. We aimed to study the association between antibiotic use (and timing of use), and the occurrence of flares in patients with RA. We nested a self-controlled case series (SCCS) of patients who have RA flares within a newly diagnosed RA cohort (n = 31,992) from the UK Clinical Practice Research Datalink (CPRD) GOLD dataset. We determined associations between exposure to antibiotics (beta-lactam, imidazole, macrolide, nitrofurantoin, quinolone, sulphonamide and trimethoprim, and tetracycline) and the occurrence of RA flares. Conditional fixed-effects Poisson regression models were used to determine incidence rate ratios (IRR), offset by the natural logarithm of risk periods. A total of 1,192 (3.7%) of RA subjects had one or more flare/s during the study period, and were therefore included. Use of sulphonamide and trimethoprim was associated with an increased risk of RA flare at 29-90 days (IRR 1.71, CI 1.12-2.59, p = 0.012); 91-183 days (IRR 1.57, CI 1.06-2.33, p = 0.025); and 184-365 days (IRR 1.44, CI 1.03-2.02, p = 0.033) after commencement of antibiotic treatment. No other antibiotic group/s appear associated with RA flare/s risk. Usage of sulphonamide and trimethoprim antibiotics, is associated with a 70% increased risk of RA flare at 1-3 months, which decreases but remains significant up to 12 months after treatment. We hypothesise that the delayed onset of RA flares after specific antibiotics is mediated through the gut or urinary microbiomes. Further epidemiological and mechanistic research is needed to determine the role of infections in RA.

Treatment of first-time traumatic anterior shoulder dislocation: the UK TASH-D cohort study.

BACKGROUND: Shoulder dislocations are the most common joint dislocations seen in emergency departments. Most traumatic cases are anterior and cause recurrent dislocations. Management options include surgical and conservative treatments. There is a lack of evidence about which method is most effective after the first traumatic anterior shoulder dislocation (TASD). OBJECTIVES: To produce UK age- and sex-specific incidence rates for TASD. To assess whether or not surgery within 6 months of a first-time TASD decreases re-dislocation rates compared with no surgery. To identify clinical predictors of recurrent dislocation. DESIGN: A population-based cohort study of first-time TASD patients in the UK. An initial validation study and subsequent propensity-score-matched analysis to compare re-dislocation rates between surgery and no surgery after a first-time TASD. Prediction modelling was used to identify potential predictors of recurrent dislocation. SETTING: UK primary and secondary care data. PARTICIPANTS: Patients with a first-time TASD between 1997 and 2015. INTERVENTIONS: Stabilisation surgery within 6 months of a first-time TASD (compared with no surgery). Stabilisation surgery within 12 months of a first-time TASD was also carried out as a sensitivity analysis. MAIN OUTCOME MEASURE: Re-dislocation rate up to 2 years after the first TASD. METHODS: Eligible patients were identified from the Clinical Practice Research Datalink (CPRD) (1997-2015). Accuracy of shoulder dislocation coding was internally validated using the CPRD General Practitioner questionnaire service. UK age- and sex-specific incidence rates for TASD were externally validated against rates from the USA and Canada. A propensity-score-matched analysis using linked CPRD and Hospital Episode Statistics (HES) data compared re-dislocation rates for patients aged 16-35 years, comparing surgery with no surgery. Multivariable Cox regression models for predicting re-dislocation were developed for the surgical and non-surgical cohorts. RESULTS: Shoulder dislocation was coded correctly for 89% of cases in the CPRD [95% confidence interval (CI) 83% to 95%], with a 'primary' dislocation confirmed for 76% of cases (95% CI 67% to 85%). Far fewer patients than expected received stabilisation surgery within 6 months of a first TASD, leading to an underpowered study. Around 20% of re-dislocation rates were observed for both surgical and non-surgical patients. The sensitivity analysis at 12 months also showed little difference in re-dislocation rates. Missing data on risk factors limited the value of the prediction modelling; however, younger age, epilepsy and sex (male) were identified as statistically significant predictors of re-dislocation. LIMITATIONS: Far fewer than the expected number of patients had surgery after a first-time TASD, resulting in an underpowered study. This and residual confounding from missing risk factors mean that it is not possible to draw valid conclusions. CONCLUSIONS: This study provides, for the first time, UK data on the age- and sex-specific incidence rates for TASD. Most TASD occurs in men, but an unexpected increased incidence was observed in women aged > 50 years. Surgery after a first-time TASD is uncommon in the NHS. Re-dislocation rates for patients receiving surgery after their first TASD are higher than previously expected; however, important residual confounding risk factors were not recorded in NHS primary and secondary care databases, thus preventing useful recommendations. FUTURE WORK: The high incidence of TASD justifies investigation into preventative measures for young men participating in contact sports, as well as investigating the risk factors in women aged > 50 years. A randomised controlled trial would account for key confounders missing from CPRD and HES data. A national TASD registry would allow for a more relevant data capture for this patient group. STUDY REGISTRATION: Independent Scientific Advisory Committee (ISAC) for the Medicines and Healthcare Products Regulatory Agency (ISAC protocol 15_0260). FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Traumatic anterior shoulder dislocation (TASD) happens when the top of the arm bone is forced frontwards out of the shoulder socket. After a TASD, the shoulder joint can become 'unstable' and keep dislocating. The main treatments are surgery or physiotherapy; however, we do not know which treatment is best at stopping more dislocations. Two large NHS computer databases were studied to assess this problem. This has allowed us to produce information on the extent of this problem in the UK. We also looked for any differences in the number of people who suffered more shoulder dislocations when treated with either surgery or no surgery. The results showed that young men aged 16­20 years and women aged > 50 years suffer the most with this problem. In young people, the cause is thought to be due to sports injuries. These findings in women aged > 50 years are new and suggest that further research is needed to discover what puts them at a greater risk of TASD. When patients who had surgery and those who did not were compared, there appeared to be no difference in the number of people suffering a re-dislocation. Although, overall, this might suggest that surgery after only one dislocation does not have any extra benefit in preventing more dislocations, this research discovered that important information used to help decide on whether or not surgical treatment is needed is not reported in the databases. Some patients may be at a greater risk of more dislocations than other patients based on risk factors, such as sport and occupation, and this information is not recorded in the NHS databases. Therefore, the research question cannot be answered by studying these NHS databases and so other methods, such as a research trial or a custom database built especially for shoulder dislocation patients, would be needed.

Opioid use, postoperative complications, and implant survival after unicompartmental versus total knee replacement: a population-based network study.

BACKGROUND: There is uncertainty around whether to use unicompartmental knee replacement (UKR) or total knee replacement (TKR) for individuals with osteoarthritis confined to a single compartment of the knee. We aimed to emulate the design of the Total or Partial Knee Arthroplasty Trial (TOPKAT) using routinely collected data to assess whether the efficacy results reported in the trial translate into effectiveness in routine practice, and to assess comparative safety. METHODS: We did a population-based network study using data from four US and one UK health-care database, part of the Observational Health Data Sciences and Informatics network. The inclusion criteria were the same as those for TOPKAT; briefly, we identified patients aged at least 40 years with osteoarthritis who had undergone UKR or TKR and who had available data for at least one year prior to surgery. Patients were excluded if they had evidence of previous knee arthroplasty, knee fracture, knee surgery (except diagnostic), rheumatoid arthritis, infammatory arthropathies, or septic arthritis. Opioid use from 91-365 days after surgery, as a proxy for persistent pain, was assessed for all participants in all databases. Postoperative complications (ie, venous thromboembolism, infection, readmission, and mortality) were assessed over the 60 days after surgery and implant survival (as measured by revision procedures) was assessed over the 5 years after surgery. Outcomes were assessed in all databases, except for readmission, which was assessed in three of the databases, and mortality, which was assessed in two of the databases. Propensity score matched Cox proportional hazards models were fitted for each outcome. Calibrated hazard ratios (cHRs) were generated for each database to account for observed differences in control outcomes, and cHRs were then combined using meta-analysis. FINDINGS: 33 867 individuals who received UKR and 557 831 individuals who received TKR between Jan 1, 2005, and April 30, 2018, were eligible for matching. 32 379 with UKR and 250 377 with TKR were propensity score matched and informed the analyses. UKR was associated with a reduced risk of postoperative opioid use (cHR from meta-analysis 0·81, 95% CI 0·73-0·90) and a reduced risk of venous thromboembolism (0·62, 0·36-0·95), whereas no difference was seen for infection (0·85, 0·51-1·37) and readmission (0·79, 0·47-1·25). Evidence was insufficient to conclude whether there was a reduction in risk of mortality. UKR was also associated with an increased risk of revision (1·64, 1·40-1·94). INTERPRETATION: UKR was associated with a reduced risk of postoperative opioid use compared with TKR, which might indicate a reduced risk of persistent pain after surgery. UKR was associated with a lower risk of venous thromboembolism but an increased risk of revision compared with TKR. These findings can help to inform shared decision making for individuals eligible for knee replacement surgery. FUNDING: EU/European Federation of Pharmaceutical Industries and Associations Innovative Medicines Initiative (2) Joint Undertaking (EHDEN).

The limitations of using simple definitions of glucocorticoid exposure to predict fracture risk: A cohort study.

PURPOSE: To evaluate the effects of different definitions of glucocorticoid (GC) exposure on the magnitude and pattern of fracture risk using the same dataset. METHODS: Data from patients with rheumatoid arthritis (RA) were extracted from the Clinical Practice Research Datalink, a primary care database with electronic health records in the United Kingdom. Patients exposed to oral GCs were matched to up to two unexposed patients by age, gender and location. The first osteoporotic fracture was identified and adjusted and unadjusted cox proportional hazard ratios (HR) and 95% confidence intervals (CI) produced for fracture risk following GC therapy using different models of risk attribution. These include models demonstrating the effect of dose, duration and recency of GC exposure. RESULTS: There were 16,507 patients included. Exposed patients were older and had more comorbidities. GC therapy was associated with an increased risk of fracture, with the effect size influenced by risk attribution model. The risk of fracture decreased with less recent exposure from HR (95% CI) 1.66 (1.27, 2.16) during the first month of stopping GCs to 1.11 (0.79, 1.57) for between 1 and 3 months. The risk of fracture increased with current daily dose, HR 1.44 (1.17, 1.77) for 5-9.9 mg prednisolone equivalent dose (PEQ) to 3.02 (1.77, 5.15) for 15-19.9 mg PEQ. Risk of fracture increased with cumulative dose, a function of dose and duration, from HR 1.22 (1.03, 1.44) for <1 g to 1.83 (1.35, 2.48) for 7.5-10 g. CONCLUSION: GC exposure was associated with excess fracture risk, with effect size differing according to definition of exposure. This highlights the need to incorporate all exposure dimensions (dose, duration and recency) in these patient's fracture risk assessments.